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The last few years have seen a dramatic increase in applications of native mass and ion mobility spectrometry, especially for the study of proteins and protein complexes. This increase has been catalysed by the availability of commercial instrumentation capable of carrying out such analyses. Like in most fields, however, the software to process the data generated from new instrumentation lags behind. Recently, a number of research groups have started addressing this by developing software, but further improvements are still required in order to realise the full potential of the datasets generated. Here we describe practical aspects as well as challenges in processing native mass spectrometry (MS) and ion mobility-MS datasets, and provide a brief overview of currently available tools. We then set out our vision of future developments that would bring the community together and lead to the development of a common platform to expedite future computational developments, provide standardised processing approaches and serve as a location for the deposition of data for this emerging field.

Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1–5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems.

Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1-5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc., link_to_OA_fulltext

The study presented below is about which variables influence the percentage of female candidates in Canadian political parties. The study is divided into two main parts: the first part being a comparison of the two main parties in Canada over 24 years in terms of the numbers of selected and elected female candidates. The second part deals with 8 variables and the amount of influence each has on the level of female candidates in Canadian political parties. The data used in my study is taken from the 2006 Canadian census on the Statistics Canada website, and election records from the official site of the Parliament of Canada. The analysis of the data was done in conjunction with analysis program called SPSS to produce cross tabulations of the 8 independent variables with the dependent variable. In the opening chapter the reader will find a discussion of the rationale for the topic and the history of women's political representation in Canada. Chapters two, three, and four describe how the methodology of my study works, the related research, and the theoretical framework. The fifth chapter contains a literature review of political parties from different nations and the state of women's representation in those nations. In the sixth chapter, the study of the elections from 1984 to 2008 to determine which party has selected and elected more female candidates is presented. The seventh chapter deals with the analysis of the data from the election study and the conclusions produced from the data. In chapter eight, the results from the electoral district survey are displayed for the reader. In chapter nine, the analysis of the results from the data from the electoral district survey is presented there. Finally, the last chapter deals with closing comments on the findings of my study and the generalizations that I think can be made from the findings. AORG351 MASV-PUBAD

We are presenting the most recent version of MEAD (v. 3.08), a large-scale public-domain summarizer that has been used in a number of applications, including the 2001 JHU summer workshop and the NewsInEssence project (www.newsinessence.com). A version of MEAD finished in first place on task 4 at DUC 2003 and finished in the top three on two other tasks.

This study examines the usefulness of common off the shelf compression software such as gzip in enhancing already existing summaries and producing summaries from scratch. Since the gzip algorithm works by removing repetitive data from a file in order to compress it, we should be able to determine which sentences in a summary contain the least repetitive data by judging the gzipped size of the summary with the sentence compared to the gzipped size of the summary without the sentence. By picking the sentence that increased the size of the summary the most, we hypothesized that the summary will gain the sentence with the most new information. This hypothesis was found to be true in many cases and to varying degrees in this study.

The production of accurate and complete multiple-document summaries is challenged by the complexity of judging the usefulness of information to the user. Our aim is to determine whether identifying sub-events in a news topic could help us capture essential information to produce better summaries. In our first experiment, we asked human judges to determine the relative utility of sentences as they related to the sub-events of a larger topic. We used this data to create summaries by three different methods, and we then compared these summaries with three automatically created summaries. In our second experiment, we show how the results of our first experiment can be applied to a cluster-based automatic summarization system. Through both experiments, we examine the use of inter-judge agreement and a relative utility metric that accounts for the complexity of determining sentence quality in relation to a topic.

BACKGROUND—Epidemiologically-based rheumatology healthcare needs assessment requires an understanding of the incidence and prevalence of musculoskeletal disorders in the community, of the reasons why people consult in primary care, and of the proportion of people who would benefit from referral to secondary care and paramedical services. This paper reports the first phase of such a needs assessment exercise. SPECIFIC OBJECTIVE—To estimate the relative frequency of musculoskeletal pain in different, and multiple, anatomical sites in the adult population. SETTING—Three general practices in the former Tameside and Glossop Health Authority, Greater Manchester, UK, a predominantly urban area. DESIGN—Population survey. METHODS—An age and sex stratified sample of 6000 adults from the three practices was mailed a questionnaire that sought data on demographic factors, musculoskeletal symptoms (pain in the past month lasting for more than a week), and physical disability (using the modified Health Assessment Questionnaire- mHAQ). The areas of pain covered were neck, back, shoulder, elbow, hand, hip, knee, and multiple joints. The Carstairs index was used as a measure of social deprivation of the postcode sector in which the person lived. RESULTS—The response rate after two reminders was 78.5%. Non-responders were more likely to live in areas of high social deprivation. People who lived in more deprived areas were also more likely to report musculoskeletal pain, especially backpain. After adjusting for social deprivation the rates of musculoskeletal pain did not differ between the practices and so their results were combined. After adjustment for social deprivation, the most common site of pain was back (23%; 95% CI 21, 25) followed by knee (19%; 95% CI 18, 21), and shoulder (16%; 95% CI 14, 17). The majority of subjects who reported pain had pain in more than one site. The prevalence of physical disability in the community rose with age. It was highest in those with multiple joint problems but was also high in those with isolated back or knee pain. CONCLUSION—Musculoskeletal pain is common in the community. People who live in socially deprived areas have more musculoskeletal symptoms. Estimates of the overall burden of musculoskeletal pain that combine the results of site specific surveys will be too high, those that do not adjust for socioeconomic factors will be too low. Keywords: prevalence; pain; social deprivation